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Europace Advance Access originally published online on March 9, 2007
Europace 2007 9(4):246-251; doi:10.1093/europace/eum018
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

ANTIARRHYTHMIC DRUGS

NIP-141, a multiple ion channel blocker, terminates aconitine-induced atrial fibrillation and prevents the rapid pacing-induced atrial effective refractory period shortening in dogs

Norio Hashimoto*, Toru Yamashita, Naoki Fujikura and Nobutomo Tsuruzoe

Biological Research Laboratories, Nissan Chemical Industries Ltd, 1470 Shiraoka, Minamisaitama, Saitama 349-0294, Japan

Manuscript submitted 20 July 2006. Accepted after revision 18 January 2007.

* Corresponding author. Tel: +81 480 92 2513; fax: +81 480 90 1014. E-mail address: hashimotot{at}nissanchem.co.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Aims NIP-141 is a novel multiple ion channel blocker with atrial selective effects. In this study, we examined the effects of NIP-141 on aconitine-induced atrial fibrillation (AF) and rapid atrial pacing-induced atrial effective refractory period (ERP) shortening in dogs.

Methods and results Aconitine AF was induced by the application of aconitine on the right appendage. NIP-141 (10 mg/kg) converted AF to sinus rhythm in 5 of 6 dogs. The Na+ channel blockers disopyramide (1 mg/kg) and phenytoin (10 mg/kg) also terminated AF, but the IKr blocker (d-sotalol; 4 mg/kg) and a Ca2+ channel blocker (verapamil; 0.3 mg/kg) did not terminate AF in this model. To clarify the mechanism of AF termination, we examined the effects on ERP and conduction time, but NIP-141 (10 mg/kg) had no significant effects. In a short-term rapid atrial pacing model, NIP-141 (2.5 mg/kg/10 min, followed by 0.033 mg/kg/min) prevented atrial ERP shortening. We also found NIP-141 bound to Na+ channel site 2 receptor and L-type Ca2+ channel, but not to Na+ channel site 1 receptor using radioligands binding assay.

Conclusion NIP-141 terminated AF in aconitine-induced AF and prevented the atrial remodelling by short-term rapid pacing in dogs, possibly via the blocking of Na+ and Ca2+ channels.

Key Words: Atrial fibrillation, Antiarrhythmic agents, Electrical remodelling, Na+ channel, Ca2+ channel


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 
Atrial Fibrillation (AF) is one of the most frequent types of arrhythmia and is a major risk factor for stroke.1Go It is also reported to double the risk of death due to cardiovascular diseases.2Go At present, AF is mainly treated with Na+ channel or K+ channel blockers.3Go–5Go However, the major problem with these agents is that they also affect ventricular excitation and repolarization. It is well known that inhibition of the rapidly activating component of delayed rectifier potassium current (IKr) in ventricular myocardium causes QT prolongation and sometimes causes life-threatening arrhythmia such as torsades de pointes.6Go Thus, atria-specific drugs are desirable for the treatment of AF.

NIP-141, (3R*,4S*)-4-cyclopropylamino-3,4-dihydro-2, 2-dimethyl-6-(4- methoxyphenylacethylamino)-7-nitro-2H-1- benzopyran-3-ol hydrochloride (hydrochloride salt of NIP-142; Figure 1), is a multiple ion channel blocker with atrial selective action potential duration (APD) prolonging profile.7Go This compound was reported to block the ultra-rapid delayed rectifier K+ current (IKur),8Go,9Go the transient outward current (Ito),8Go acetylcholine-activated K+ current (IKACh),7Go and L-type and T-type Ca2+ currents.10Go NIP-141 was also shown to terminate AF in canine vagal nerve stimulation-induced AF model with selective atrial effective refractory period (ERP) prolongation.11Go This model can be suitable for examining antiarrhythmic drug efficacy, because vagal stimulation shortens atrial APD and ERP, and increases dispersion of atrial repolarization, which creates an arrhythmogenic substrate for AF,12Go and the enhancement of vagal activity could be responsible for initiation of paroxysmal AF.13Go However, the pathogenesis of the AF patient is more complex. Thus, investigations using various types of AF models are needed to make a prediction of drug effectiveness.


Figure 1
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  		Figure 1 Chemical structure of NIP-141, (3R*,4S*)-4-cyclopropylamino-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacethylamino)-7-nitro-2H-1-benzopyran-3-ol hydrochloride.

 
In the present study, we examined the effects of NIP-141 on aconitine-induced (focal activity-induced) AF model14Go and compared with the effects of Na+ channel blockers (disopyramide and phenytoin), an IKr blocker (d-sotalol) and a Ca2+ channel blocker (verapamil). We also examined the effects on ERP shortening induced by short-term atrial rapid pacing to clarify the effects of NIP-141 on atrial electrical remodelling. In addition, we examined the effects of NIP-141 on ERP and conduction time in anaesthetized dogs, and the binding affinity for Na+ channel and Ca2+ channel to clarify the mechanism of the action.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
Animal experiments were conducted according to the Guideline for Animal Experimentation by the Japanese Association for Laboratory Animal Science (1987). All experimental protocols were approved by the Ethics Review Committee for Animal Experimentation of Nissan Chemical Industries.

Aconitine-induced model
Thirty five beagle dogs (Oriental Yeast Co. Ltd., Tokyo, Japan) of either sex weighing 8–12 kg were anaesthetized with pentobarbital (30 mg/kg, i.v.), supplemented during the experiment as needed. Each animal was intubated and respiration was maintained with room air, delivered via a respirator. Forearm and femoral veins were cannulated for administration of drugs and maintenance of fluid balance, respectively. The chest was opened by right thoracotomy and the heart was exposed via incision in the pericardium. Two bipolar electrodes were placed in low right atrium and right ventricular free wall for recording, respectively.

Atrial fibrillation was induced by the application of aconitine (0.1 mg/body) impregnated absorbent cotton on the right appendage. Two min after the onset of AF, each drug (3 or 10 mg/kg of NIP-141, 1 mg/kg of disopyramide, 10 mg/kg of phenytoin, and 4 mg/kg of d-sotalol, or 0.3 mg/kg of verapamil) or vehicle was intravenously administrated. The choices of drug doses were based on the published data.15Go–18Go We evaluated whether AF was interrupted within 10 min after each drug administration.

Measurement of ERP and conduction time
Fifteen beagle dogs of either sex weighing 8–12 kg were anaesthetized with pentobarbital. The chest was opened by right thoracotomy and three bipolar electrodes were placed on the right atrial appendage, low right atrium and right ventricular free wall for pacing and recording. The ERP was determined using a train of 10 basic (S1) stimuli followed by a premature (S2) stimulus. Basic cycle length (BCL) was 200 and 300 ms in low right atrium and 300 ms in right ventricle. S2 was initially delivered late in diastole and moved in 10-ms decrements until a response was not elicited by S2. The procedure was then repeated over the final 10-ms window in 2-ms decrements. The ERP was defined as the longest S1–S2 interval failing to propagate a response. The conduction time (CT) from the low to atrial appendage was determined at a BCL of 300 and 200 ms. Then, NIP-141 (3 or 10 mg/kg) or vehicle was intravenously administrated. ERP and CT measurements were repeated 5 min after drug administration. Results were shown as variation between before and 5 min after vehicle or NIP-141 administration.

Short–term atrial rapid pacing model
Eighteen male mongrel dogs (HBD dog, Oriental Yeast Co. Ltd.), weighing 18–24 kg, were anaesthetized with pentobarbital (30 mg/kg followed by 5 mg/kg/h, i.v.). The chest was opened by thoracotomy and two bipolar electrodes were placed in low right atrial appendage and free wall for rapid pacing and ERP measurement, respectively. Autonomic blockade was achieved in all animals with an initial bolus of atropine and atenolol (0.04 mg /kg and 0.2 mg/kg), followed by maintenance infusion for the duration of the experiment (0.007 and 0.04 mg/kg/h). The ERP at BCL 400 was determined as previously described.

After baseline ERP measurement, dogs received an intravenous injection of NIP-141 (2.5 mg/kg/10 min, followed by 0.033 mg/kg/min) or an equivalent volume of vehicle. The dose level for NIP-141 was predicted to give rise to pseudo-steady state plasma concentration of 1 µg/mL. Atrial ERP was measured 30 min after the initiation of drug infusion to determine the direct effects on ERP. Rapid atrial pacing was immediately initiated at 600 bpm at output of 10 V. Effective refractory period was measured at 15, 30, 60, 120, 180, and 240 min after the initiation of rapid pacing. Rapid pacing was interrupted before every ERP measurement, but not for >2 min. At 240 min after the initiation of rapid pacing, the ERPs at a BCL 300 and 200 ms were also determined to clarify the effects on rate adaptation.

Binding assay
To analyse drug effects, membranes were prepared from rat forebrain (Na+ channels) or rat cerebral cortex (Ca2+ channel). Saxitoxin, batrachotoxin, and nitrendipine bind to allosteric site 1 and site 2 on voltage-gated Na+ channel and dihydropirydine (DHP) site on L-type Ca2+ channel with an equilibrium constant (Kd) of 2.2, 32 and 0.2 nM, respectively.

[H3]Saxitoxin binding reactions were carried out in 130 mM choline chrolide (pH 7.4) at 37°C for 60 min, [H3]Batrachotoxin binding reactions were carried out in 50 nM HEPES (pH 7.4) containing 130 mM choline chloride at 35°C for 45 min and [H3]Nitrendipine binding reactions were carried out in 50 mM Tris–HCl (pH 7.7) at 37°C for 60 min to ascertain any interaction of 0, 1, 10, 100 µM NIP-141 with the sodium channel site 1 binding site, site 2 binding site and the calcium channel DHP binding site, respectively. The reactions were terminated by rapid vacuum filtration onto glass fibre filters. Non-specific bindings were determined in the presence of 1.0 µM tetrodotoxin, 200 µM aconitine, and 1.0 µM nifedipine, respectively.

Drugs
NIP-141 and d-sotalol were synthesized with Nissan Chemical Industries Ltd (Funabashi, Japan). Any other test compounds were purchased from Sigma Chemical Co. (St. Louis, MO, USA). All test compounds were diluted with polyethylene glycol NO. 400: ethanol: distilled water, 2: 3: 5.

Statistical analysis
All data were expressed as mean ± SEM, except for the incidence of AF. For evaluation of the differences in the incidence of AF, Fisher's exact test was used. For evaluation of the effects of NIP-141 on ERP and conduction time and the influences of rapid atrial pacing, one-way analysis of variance (ANOVA) followed by a post-hoc Dunnett's test was used. For evaluation of ERP and rate adaptation of ERP in three groups and atrial ERP change from baseline in rapid pacing model, Dunnett's test was used. P values less than 0.05 were considered statically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
Aconitine-induced AF model
An average AF cycle length was about 40–50 ms in this model. As shown in Table 1, NIP-141 (10 mg/kg) converted AF to sinus rhythm in five of six dogs in aconitine-induced AF model. Typical traces of AF termination by 10 mg/kg of NIP-141 are shown in Figure 2. The Na+ channel blockers disopyramide (1 mg/kg) and phenytoin (10 mg/kg) also terminated AF in this model. In contrast, d-sotalol (4 mg/kg) and verapamil (0.3 mg/kg) did not terminate AF in this model.


Figure 2
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  		Figure 2 A representative example of termination of AF with NIP-141 at 10 mg/kg. Atrial electrograms were recorded from low right atrium. (A) Baseline electrogram, (B) AF before drug injection, and (C) termination of AF.

 


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  		Table 1 Effects of NIP-141, disopyramide, phenytoin, d-sotalol, and verapamil in terminating aconitine-induced atrial fibrillation (AF)

 
Effects on ERP and conduction time
To clarify the mechanism of AF termination by NIP-141, we examined the effects on ERP and intraatrial conduction time as an index of conduction velocity. As shown in Figure 3A, NIP-141 (3, 10 mg/kg) had no significant effects on both atrial and ventricular ERP. Atrial and ventricular ERP from 136 ± 7 ms and 163 ± 14 ms to 138 ± 7 ms and 163 ± 12 ms in vehicle treated group, and from 146 ± 5 ms and 173 ± 10 ms to 150 ± 7 ms and 174 ± 8 ms in 10 mg NIP-141 treated group. Intraatrial conduction times at BCL of 300 ms and 200 ms were also not affected by NIP-141 (Figure 3B).


Figure 3
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  		Figure 3 Effects of NIP-141 (3 or 10 mg/kg, i.v.) and vehicle on (A) atrial and ventricular ERP and (B) conduction time at BCL of 300 and 200 ms in anaesthetized dogs. Results were shown as variation between before and 5 min after vehicle or NIP-141 administration. Data are expressed as mean ± SEM (n = 5 within each group).

 
Short-term rapid pacing model
Figure 4A shows the time course of atrial ERP at BCL of 400 ms (AERP400) changes with rapid pacing in pace/vehicle and pace/NIP-141 groups and without rapid pacing (non-pace/vehicle) group. In pace/vehicle group, after the initiation of rapid pacing, AERP400 shortened from 151 ± 8 ms at the baseline to 137 ± 9 ms at 15 min. This shortening persisted throughout the study (138 ± 8 ms at 4 h). Atrial fibrillation episodes (spontaneously terminated in seconds) were observed in two of six pace/vehicle dogs after stopping rapid atrial pacing. On the other hand, AERP400 in non-pace/vehicle dogs gradually increased throughout the study (from 152 ± 7 ms at the baseline to 177 ± 13 ms at 4 h).


Figure 4
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  		Figure 4 (A) Time course of atrial ERP changes with rapid atrial pacing in pace/NIP-141 dogs and pace/vehicle dogs and without rapid pacing in non-pacing/vehicle dogs. Effective refractory period was measured at BCL of 400 ms. (B) Rate adaptation of atrial ERP in pace/NIP-141 dogs, pace/vehicle dogs and non-pacing/vehicle dogs. Y-axis denotes difference in ERP at BCL of 300 and 200 ms from that at BCL of 400 ms. ERP was measured at 4 h after the start of rapid atrial pacing. Data are expressed as mean ± SEM (n = 6 within each group). *P < 0.05, **P < 0.01 vs. non-pace/vehicle group. *P < 0.05, **P < 0.01 vs. the baseline value of each group (time 0).

 
After infusion of NIP-141, before the initiation of rapid pacing, AERP400 did not significantly change: from 143 ± 9 ms to 148 ± 8 ms after the infusion of NIP-141 (P = 0.35; paired Student's t-test). With the initiation of pacing, similar to non-pace/vehicle group, AERP400 gradually increased in pace/NIP-141 dogs with 145 ± 8 ms at 15 min and 167 ± 8 ms at 4 h rapid pacing. No AF episode was observed in pace/NIP-141 dogs.

A marked decrease in the ERP adaptation to rate was reportedly observed in AF patients and rapid pacing model.19Go,20Go Thus, we tested the effects of NIP-141 to the rate maladaptation. Figure 4B shows that rate adaptation of atrial ERP after 4 h rapid pacing. In non-pace/vehicle group, atrial ERP at BCL 300 ms (AERP300) and BCL 200 ms (AERP200) shortened by –11.7 ± 3.4 ms and –53.0 ± 7.3 ms from AERP400, respectively. In contrast, in pace/vehicle group, AERP300 and AERP200 shortened by 2.0 ± 2.3 ms and –14.3 ± 3.8 ms from AERP400, respectively. This result shows that the rate adaptation was blunted by atrial rapid pacing. In pace/NIP-141 group, AERP300 and AERP200 shortened by –7.7 ± 3.0 ms and –44.0 ± 6.6 ms from AERP400, which was not significantly different from the non-pace/vehicle group.

Binding assay
We tested the inhibitory effects of NIP-141 to [H3]sarafotoxine, [H3]batrachotoxin [H3]nitrendipine binding to evaluate the effects on Na+ channel site 1 receptor, site 2 receptor, and L-type Ca2+ channel, respectively. NIP-141 inhibited [H3]Batrachotoxin binding and [H3]Nitrendipin binding, with IC50 of 45 and 44 µM and Hill coefficients of 1.7 and 1.3, respectively (n = 1, duplicate). In contrast, NIP-141 did not inhibit [H3]Saxitoxin binding (16% inhibition at 100 µM; n = 1, duplicate).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
In this study, we found that the novel multiple ion channel blocker NIP-141 converted AF to sinus rhythm in the aconitine-induced AF model. However, the precise mechanism of AF termination in this model is unclear, because NIP-141 had no effects on atrial ERP and intraatrial conduction time as an index of conduction velocity. IKr and L-type Ca2+ channel may not have an important role in the pathogenesis of this model, because IKr blocker d-sotalol and L-type Ca2+ channel blocker verapamil were not effective. Aconitine is well known as an inhibitor of voltage-dependent Na+ channel inactivation21Go and causes intracellular Na+ accumulation. Intracellular Na+ accumulation causes an influx of Ca2+ via reverse mode of Na+/Ca2+ exchanger (NCX) activation and promotes arrhythmogenesis by a variety of mechanisms.22Go Thus, it is reasonable that Na+ channel blockers, disopyramide and phenytoin, suppressed intracellular Na+ accumulation and terminated AF in this model. NIP-141 did not bind to sarafotoxin-sensitive Na+ channel site 1 receptor, but bound to batrachotoxin-sensitive Na+ channel site 2 receptor, to which aconitine binds.23Go The effects of NIP-141 in inhibiting the binding of [H3]batrachotoxin (IC50=45 µM) is similar to that of phenytoin (IC50=41 µM).24Go The effective dose of NIP-141 is also similar to that of phenytoin in aconitine-induced AF model. Thus, AF termination by NIP-141 might be due to the inhibition of Na+ uptake by aconitine.

The pathophysiological role of Na+ channel site 2 receptor in AF has not been elucidated. In the ventricle, several studies showed that some blockers of veratridine-induced Na+ influx via Na+ channel site 2 receptor prevents ischaemia/reperfusion-induced arrhythmia in a variety of models.25Go,26Go These results suggest that reducing intracellular Na+ accumulation exerts antiarrhythmic effects, at least in ischaemia-induced arrhythmia. Recent evidence suggests that the histopathology of atria in chronic AF is similar to that of chronically ischaemic ventricular myocardium.27Go In addition, Jayachandran et al. have reported that chronic AF is associated with a reduction in atrial myocardial blood flow.28Go Thus, the blockade of Na+ channel site 2 receptor might be effective for the treatment of some type of chronic AF.

NIP-141 also prevented atrial ERP shortening and rate maladaptation of atrial ERP induced by rapid atrial pacing. It is unlikely that the effect of NIP-141 was due to the direct ERP prolongation, because the dose of NIP-141 had no significant effects on atrial ERP before pacing. Although the correlation of various ion channels and/or intracellular junctions with electrical remodelling has been reported,29Go,30Go the initial key to these changes is intracellular calcium overload, especially in the early phase. Several studies have shown that the some L-type Ca2+ channel blockers prevents atrial ERP shortening caused by rapid pacing.30Go–32Go We found that NIP-141 bound to L-type Ca2+ channel DHP site. In addition, Matsuda et al. showed that NIP-141 blocked L-type and T-type Ca2+ channels using patch clamp methods.7Go Thus, it is likely that the prevention of ERP shortening by NIP-141 is also due to blockade of the Ca2+ channel. As another possibility, we considered that inhibition of Na+ uptake might be related to the prevention of electric remodelling, because the pure sodium channel blocker pilsicainide reportedly prevented atrial remodelling induced by rapid pacing via a reduction of intracellular Ca2+.33Go

The effect of NIP-141 on electrical remodelling was observed only in the short-term rapid atrial pacing mode, but not in the long-term rapid atrial pacing model. The effect of the L-type Ca2+ channel blocker verapamil suppresses the shortening of atrial ERP, in relatively short-term (<24 h),30Go,31Go but not relatively long-term (1 and 6 weeks) rapid atrial pacing model.34Go On the other hand, the L-type and T-type Ca2+ channel blockers, efonidipine reportedly prevented atrial ERP shortening induced by rapid atrial pacing, at least over the study period of 14 days, which was significantly longer than the effect exerted by the L-type Ca2+ channel blocker verapamil.32Go Fareh et al. also found that the T-type Ca2+ channel blocker mibefradil prevented atrial ERP shortening caused by 7 days rapid pacing.35Go In addition, T-type Ca2+ current has been reported to remain unaffected even after 6-weeks pacing.19Go These studies suggest that T-type Ca2+ channel has a crucial role in atrial remodelling in long-term rapid pacing model. NIP-141 blocks not only L-type (IC50 = 10 µM) but also T-type Ca2+ channel (IC50=54 µM) in guinea pig's ventricular muscle cells.7Go Thus, it is likely that this compound can prevent atrial remodelling by long-term rapid pacing. Further studies are needed using the long-term rapid pacing model.

Study limitations
Our study has some limitations. First, we used the aconitine-induced AF model. However, this model is not relevant to clinical AF, because of normal heart. Thus, further investigation using the AF model with remodelled atria would be needed. Second, we measured ERP and CT at BCL of 300 and 200 ms. The cycle length was <75 ms in aconitine-induced AF. We will have to measure ERP at the shorter BCL to clarify the precise mechanism. Third, the drug effects on radioligand binding do not necessarily reflect effects on target function, although considerable evidence supported such a correlation for many targets. Further studies using the patch clamp technique would be needed to clarify the mechanism of action.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
NIP-141 converted AF to sinus rhythm in aconitine-induced AF and prevented the atrial remodelling by short-term rapid pacing in dogs, possibly via the blocking of Na+ and Ca2+ channels.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
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I. Savelieva and J. Camm
Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches
Europace, June 1, 2008; 10(6): 647 - 665.
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